Obesity and diabetes-related disorders have increasingly great prevalence in the western world. Coronary heart disease is the main cause of death among many populations. Due to dietary and genetic causes, atherosclerosis affects over a million people each year with cardiac manifestations. The presence of lysophosphatidylcholine and other inflammatory molecules in the atheroma have led to inquiries regarding the role of phospholipases in the development of atherosclerosis. As the number of phospholipases is large, detailing the contribution of each one is not yet complete. Recent studies have linked human polymorphisms of the group 1B phospholipase A2 gene (PLA2G1B) with increased central adiposity, which is a risk factor for cardiovascular disease. Phospholipase A2 group 1B is a digestive enzyme that aids digestion by selectively catalyzing the conversion of phospholipids in the gut lumen to lysophosphatidylcholine (LPC) and fatty acid. Mice deficient in this enzyme retain the ability to digest dietary lipids due to compensatory enzymes, but do not produce LPC to a similar extent. Furthermore, Pla2g1b-/- mice are resistant to diet-induced obesity, diet-induced type-2 diabetes, and diet-induced hyperlipidemia. The mechanism involves increased fatty acid metabolism, decreased hepatic very-low-density lipoprotein (VLDL) production, and increased post-prandial triglyceride rich lipoprotein clearance. However, the specific subcellular details of how plasma LPC alters hepatocyte metabolism are not known. Furthermore, it is not known whether genetic inhibition of Pla2g1b leads to a decreased risk of atherosclerosis in vivo. This proposal addresses these concerns by testing the ex vivo, in vitro, and in vivo effects of Pla2g1b inhibition and the addition of its enzymatic product, LPC. Mitochondria will be isolated and the effects of LPC upon membrane integrity and potential will be determined. The effect of LPC upon fatty acid metabolism in isolated hepatocytes will also be ascertained. Furthermore, the effect of Pla2g1b competence upon atherosclerosis development and systemic inflammation will be investigated in a mouse model of diet-induced atherosclerosis.